rs63750083

Positions:

• chr14-73219177-C-A
• chr14-73219177-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000324501.10(PSEN1):​c.1292C>A​(p.Ala431Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A431V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN1 ENST00000324501.10 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.83

Genes affected

PSEN1 (HGNC:9508): (presenilin 1) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in ENST00000324501.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-73219177-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 98113.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, not_provided=1}.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PSEN1. . Gene score misZ 2.1558 (greater than the threshold 3.09). Trascript score misZ 3.0986 (greater than threshold 3.09). GenCC has associacion of gene with acne inversa, familial, 3, dilated cardiomyopathy, Alzheimer disease 3, early-onset autosomal dominant Alzheimer disease, semantic dementia, Pick disease, familial isolated dilated cardiomyopathy, dilated cardiomyopathy 1U, behavioral variant of frontotemporal dementia.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 14-73219177-C-A is Pathogenic according to our data. Variant chr14-73219177-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 18155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-73219177-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN1	NM_000021.4	c.1292C>A	p.Ala431Glu	missense_variant	12/12	ENST00000324501.10	NP_000012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN1	ENST00000324501.10	c.1292C>A	p.Ala431Glu	missense_variant	12/12	1	NM_000021.4	ENSP00000326366	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 30, 2023	The PSEN1 c.1292C>A; p.Ala431Glu (rs63750083) variant is reported in the literature in several individuals and families with Alzheimer's disease (Parker 2019, Portelius 2010, Soosman 2016) and is implicated as a founder variant in individuals from Jalisco state in Mexico (Murrell 2006). The variant is reported in the ClinVar database as pathogenic by several sources (Variation ID: 18155) but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 431 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.946). Functional studies indicate this variant inhibits gamma secretase activity and impair its function as a calcium leak channel (Nelson 2010, Sun 2017). Based on available information, this variant is classified as pathogenic. References: Murrell J et al. The A431E mutation in PSEN1 causing familial Alzheimer's disease originating in Jalisco State, Mexico: an additional fifteen families. Neurogenetics. 2006 Nov;7(4):277-9. Nelson O et al. Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. J Alzheimers Dis. 2010;21(3):781-93. Parker J et al. Homozygosity for the A431E mutation in PSEN1 presenting with a relatively aggressive phenotype. Neurosci Lett. 2019 Apr 23;699:195-198. Portelius E et al. Distinct cerebrospinal fluid amyloid beta peptide signatures in sporadic and PSEN1 A431E-associated familial Alzheimer's disease. Mol Neurodegener. 2010 Jan 14;5:2. Soosman SK et al. Widespread white matter and conduction defects in PSEN1-related spastic paraparesis. Neurobiol Aging. 2016 Nov;47:201-209. Sun L et al. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of AB42 and AB40 peptides by gamma-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 16, 2022	This variant has been identified in multiple unrelated individuals with autosomal dominant Alzheimer disease and is considered the most common cause of Alzheimer disease among individuals of Mexican ancestry (PMID: 16628450, 16897084, 33274538). This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. A study shows this variant results in increased amyloid-beta 42 peptide production (PMID: 27930341). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2023	Published functional studies demonstrate a damaging effect (Nelson et al., 2010; Sun et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27614114, 20634584, 20145736, 27930341, 26756738, 30716424, 11524469, 16628450, 16801675, 16897084, 31884479, 33274538) -

Alzheimer disease 3 Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2022	Variant summary: PSEN1 c.1292C>A (p.Ala431Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes. c.1292C>A has been widely reported in the literature in multiple individuals affected with Alzheimer Disease, Type 3 and is regarded as a founder variant of Mexican origin (example, Murrell_2006). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function demonstrating a modulation of the gamma secretase activity and an increased ratio of long A-beta APP (amyloid precursor protein) cleavage fragments over shorter ones, exemplified by the ratio of A-beta42 over A-beta 40, consistent with the established pathophysiology of disease (example, Portelius_2010, Sun_2017). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Pick disease;C0338451:Frontotemporal dementia;C1843013:Alzheimer disease 3;C3151038:Acne inversa, familial, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 431 of the PSEN1 protein (p.Ala431Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Alzheimer disease (PMID: 16628450, 16897084). It is commonly reported in individuals of Mexican ancestry (PMID: 16628450, 16897084). ClinVar contains an entry for this variant (Variation ID: 18155). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PSEN1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PSEN1 function (PMID: 20145736, 20634584, 21373759, 27930341). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	.;D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.7	.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;.;.
Vest4		0.97
MutPred		0.77		.;Gain of catalytic residue at L432 (P = 0);.;.;.;
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63750083; hg19: chr14-73685885;